Sachet Formulation for Amine Polymers

ABSTRACT

A powder formulation comprises a pharmaceutically acceptable anionic stabilizer and an aliphatic amine polymer or a pharmaceutically acceptable salt thereof mixed with the anionic stabilizer. The powder formulation is conveniently packaged in a container, such as a sachet. A method of treating a subject with hyperphosphotemia with the powder formulation is also disclosed.

BACKGROUND OF THE INVENTION

Aliphatic amine polymers are effective as phosphate binders and havebeen described for the treatment of various conditions (see U.S. Pat.Nos. 5,496,545 and 5,667,775). For example, sevelamer hydrochloride, acrosslinked poly(allylamine) polymer, is currently sold under thetrademark of RENAGEL® for removing phosphate from patients. Aliphaticamine polymers have also been described for the treatment ofhypercholoestrolemia (see U.S. Pat. Nos. 5,624,963 and 5,679,717 and PCTPublication Nos. WO98/29107 and WO99/22721). For example, colesevelam,an alkylated, crosslinked poly(allylamine), is currently sold under thetrademark of WELCHOL® for reducing serum cholesterol.

However, as the above products are currently available only as tablets,certain patient groups may benefit from the availability of theseproducts in other dosage forms.

SUMMARY OF THE INVENTION

The present invention provides for, inter alia, new compositions andformulations of aliphatic amine polymers. One such formulation is apowder formulation that can be mixed with water and administered orallyas a drink (solution or, suspension), while providing acceptableproperties to the patient such as mouth feel and taste. Applicants havefound that in such formulations, a pharmaceutically acceptable anionicstabilizer, when mixed with the aliphatic amine polymer, can provideacceptable mouth-feel of an aliphatic amine polymer. Based on thisdiscovery, a novel powder formulation for aliphatic amine polymer or apharmaceutically acceptable salt thereof, a container containing thepowder formulation and a method of treating a subject havinghyperphosphatemia with the powder formulation are disclosed herein.

In one embodiment, the present invention provides for a containercontaining a powder that comprises a pharmaceutically acceptable anionicstabilizer and an aliphatic amine polymer or a pharmaceuticallyacceptable salt thereof mixed with the anionic stabilizer. The powder isuncapsulated and free-flowing.

In another embodiment, the present invention is a powder formulationcomprising a pharmaceutically acceptable anionic stabilizer and analiphatic amine polymer or a pharmaceutically acceptable salt thereofmixed with the pharmaceutically acceptable anionic stabilizer.Preferably, the only pharmaceutically active ingredient in the powder isthe aliphatic amine polymer.

The present invention also provides a method of treating a subject withhyperphosphatemia. The method comprises the step of orally administeringto the subject the disclosed powder formulation.

DETAILED DESCRIPTION OF THE INVENTION

The disclosed powder formulation comprises an aliphatic amine polymerand a pharmaceutically acceptable anionic stabilizer formulated so as toprovide an acceptable mouth-feel. The powder formulation is typicallydissolved and/or suspended in an ingestible liquid such as water andtherefore can be conveniently administered to a patient as a drink. Thedrink can be even more palatable with one or more sweeteners and/orflavorants. Such powder formulations may be conveniently packaged in acontainer, such as a sachet or tub. As used herein, the terms “powder”and “powder formulation” are used interchangeably.

The powder formulations of the present invention may further compriseflavorants, sweeteners, excipients, fillers, inert ingredients and thelike.

As used herein, “a pharmaceutically acceptable anionic stabilizer” is acompound which comprises an acid functional group (e.g., a carboxylicacid, sulfonic acid, phosphoric acid and the like, or a pharmaceuticallyacceptable salt thereof), and may substantially improve the mouth-feelof aliphatic amine polymers. The acid functional group is optionallyneutralized with one or more pharmaceutically acceptable organic orinorganic bases to form a pharmaceutically acceptable salt. When thepharmaceutically acceptable anionic stabilizer includes more than oneacid functional group, the acid functional groups can be partially orcompletely neutralized. Optionally, some of the acid functional groupscan be esterified to form an ester of the acid functional group.Examples of organic or inorganic bases are, as described below.

The pharmaceutically acceptable anionic stabilizer typically has asolubility in water of greater than 1 mg/ml and a pKa value less than 9.The pharmaceutically acceptable anionic stabilizer should not interferewith the therapeutic activity of the aliphatic amine polymers, andshould not cause unacceptable side effects at the dosages which arebeing administered.

The molecular weight of the pharmaceutically acceptable anionicstabilizer is not critical in the present invention as long as it hasthe features described above. Typically, the molecular weight of thepharmaceutically acceptable anionic stabilizer is greater than 1000daltons. When the molecular weight of the pharmaceutically acceptableanionic stabilizer is greater than 1000 daltons, the charge density ofthe pharmaceutically acceptable anionic stabilizer is typically equal toor greater than 1 every 1000 daltons.

The pharmaceutically acceptable anionic stabilizer may not be a“pharmaceutically active ingredient”.

In one embodiment, the pharmaceutically acceptable anionic stabilizer isan anionic polymer, such as an anionic polypeptide (e.g., a protein), ananionic polysaccharide or a polymer of one or more anionic monomers.Examples of anionic polymers include polymers of mannuronic acid,guluronic acid, acrylic acid, methacrylic acid, glucuronic acid,glutamic acid or a combination thereof, and pharmaceutically acceptablesalts thereof. Other examples of anionic polymers include cellulose,such as a carboxyalkyl cellulose or a pharmaceutically acceptable saltthereof. An anionic polymer can be a homopolymer or a copolymer of twoof the anionic monomers described above. Alternatively, the anioniccopolymer comprises one or more repeat units of the anionic monomersdescribed above and one or more neutral comonomers which are preferablyinert and non-toxic. Examples of suitable neutral comonomers which canbe used with, for example, olefinic anionic monomers, include vinylalcohol, acrylamide and vinylformamide. Specific examples of anionicpolymers include alginate (e.g., sodium alginate, potassium alginate,calcium alginate, magnesium alginate, ammonium alginate, esters ofalginate, etc.), carboxymethyl cellulose, poly lactic acid, polyglutamic acid, pectin, xanthan, carrageenan, furcellaran, gum arabic,karaya gum, gum ghatti, gum carob and gum tragacanth.

In a preferred embodiment, the anionic polymer is an alginate, morepreferably an esterified alginate, such as a C2-C5-diol ester ofalginate or a C3-C5-triol ester of alginate. As used herein, an“esterified alginate” means an alginic acid in which some of thecarboxyl groups of the alginic acid are esterified. The remainder of thecarboxylic acid groups are optionally neutralized (partially orcompletely) as pharmaceutically acceptable salts. For example, propyleneglycol alginate is an ester of alginic acid in which some of thecarboxyl groups are esterified with propylene glycol, and the remainderof the carboxylic acid groups are optionally neutralized (partially orcompletely) as pharmaceutically acceptable salts. More preferably, theanionic polymer is ethylene glycol alginate, propylene glycol alginateor glycerol alginate. Propylene glycol alginate is even more preferred.

As noted above, the anionic polymer can be used in the form of apharmaceutically acceptable salt (completely or partially neutralized).As used herein, a “pharmaceutically acceptable salt” refers to a saltprepared from pharmaceutically acceptable acids or bases. For example,the anionic polymers that possess a sufficiently acidic functional groupcan react with any of a number of pharmaceutically acceptable organic orinorganic bases to form a salt. Examples of salts include alkali metaland alkali earth metals, such as sodium, calcium, magnesium andpotassium; zinc; and ammonium salts. Mixed salts are also included.“Ammonium” can be represented as NR′₄ ⁺ where R′ is —H or substituted orunsubstituted, linear or cyclic, or saturated or unsaturated alkyl, arylor araryl. Examples of the ammonium include NH₄ ⁺ and N(R′)H₃ ⁺,N(R′)₂H₂ ⁺, N(R′)₃H⁺ and N(R′)₄ ⁺, where R′ is C1-C10 alkyl or phenyl.

In another embodiment, the pharmaceutically acceptable anionicstabilizer is an anionic polypeptide, including a protein. Examples ofanionic polypeptides include gelatin, casein digest, whey protein, soyprotein and polyglutamic acid.

One or more pharmaceutically acceptable anionic stabilizers can be usedin the present invention.

The powder formulations of the invention typically include thepharmaceutically acceptable anionic stabilizer and aliphatic aminepolymer in a ratio of 0.005-99.9:1 by weight, such as 0.005-50:1,0.005-10:1; 0.005-3:1, 0.005-1:1, 0.005-0.05:1, and 0.008-0.05:1.

Aliphatic amine polymers are characterized by a repeat unit thatincludes at least one amine group. Amine groups can be part of thepolymer backbone (e.g., a polyalkyleneimine such as polyethyleneimine)or pendant from the polymer backbone (e.g., polyallylamine).Alternatively, both types of amine groups can exist within the samerepeat unit and/or polymer. The word “amine,” as used herein, includesprimary, secondary and tertiary amines, as well as ammonium groups suchas trialkylammonium.

An aliphatic amine polymer may be obtained by polymerizing an aliphaticamine monomer. An aliphatic amine is saturated or unsaturated,straight-chained, branched or cyclic non-aromatic hydrocarbon having anamino substituent and optionally one or more additional substituents. Analiphatic amine monomer is an aliphatic amine comprising a polymerizablegroup such as an olefin. Suitable aliphatic amine polymers are describedin U.S. Pat. Nos. 5,487,888, 5,496,545, 5,607,669, 5,618,530, 5,624,963,5,667,775, 5,679,717, 5,703,188, 5,702,696, 5,693,675, 5,900,475,5,925,379, 6,083,497, 6,177,478, 6,083,495, 6,203,785, 6,423,754,6,509,013, 6,605,270, 6,726,905, 6,733,780 and 6,858,203 and U.S.Published Applications Nos. 2002/0159968 A1 and 2003/0086898 A1, thecontents of which are incorporated herein by reference in theirentireties.

An aliphatic amine polymer may be a homopolymer or a copolymer of one ormore amine-containing monomers or a copolymer of one or moreamine-containing monomers in combination with one or more non-aminecontaining monomers, which are preferably inert and non-toxic. Examplesof suitable non-amine-containing monomers include vinyl alcohol, acrylicacid, acrylamide, and vinylformamide.

Examples of aliphatic amine polymers include polymers that have one ormore repeat units selected from Formulas (1)-(6):

or a salt or copolymer thereof, where y is zero or an integer of one ormore (e.g., between about one and about 10, preferably between one andfour, more preferably one) and each R, R₁, R₂, and R₃, independently, isH, a substituted or unsubstituted alkyl group (e.g., having between 1and 25 or between 1 and 5 carbon atoms, inclusive) or aryl (e.g.,phenyl) group, and each X⁻ is an exchangeable negatively chargedcounterion.

Preferably, at least one of R, R₁, R₂, or R₃ is a hydrogen atom. Morepreferably, each of these groups is hydrogen.

The alkyl or aryl group, represented by R, R₁, R₂, and R₃, can carry oneor more substituents. Suitable substituents include cationic groups,e.g., quaternary ammonium groups, or amine groups, e.g., primary,secondary or tertiary alkyl or aryl amines. Examples of other suitablesubstituents include hydroxy, alkoxy, carboxamide, sulfonamide, halogen,alkyl, aryl, hydrazine, guanidine, urea, poly(alkyleneimine) such aspoly(ethylenimine), and carboxylic acid esters.

Preferably, an aliphatic amine polymer is a homopolymer, such as ahomopolyallylamine, homopolyvinylamine, homopolydiallylamine orpolyethyleneamine.

In one embodiment, the aliphatic amine polymer is a homopolymer orcopolymer characterized by one or more repeat units of StructuralFormula (7):

or a pharmaceutically acceptable salt thereof, where x is 0 or aninteger between 1 and 4, preferably 1. The polymer represented byStructural Formula (7) is advantageously crosslinked by means of across-linking agent.

A preferred aliphatic amine polymer for use in the invention ispolyallylamine, which is a polymer having repeat units from polymerizedallyl amine monomers. The amine group of an allyl monomer can beunsubstituted or substituted with, for example, one or two C1-C10straight chain or branched alkyl groups. These alkyl groups areoptionally substituted with one or more hydroxyl, amine, halo, phenyl,amide or nitrile groups. Preferably, the aliphatic amine polymers ofpresent invention are polyallylamine polymers comprising repeat unitsrepresented by Structural Formula (8):

Polyallylamines that may be used as the aliphatic amine polymers of thepresent invention may include copolymers comprising repeat units fromtwo or more different polymerized allyl monomers or with repeat unitsfrom one or more polymerized allyl monomers and repeat units from one ormore polymerized non-allyl monomers. Examples of suitable non-allylmonomers include acrylamide monomers, acrylate monomers, maleic acid,malimide monomers, vinyl acylate monomers and alkyl substitutedolefines. Preferably, however, the polyallylamines used in the presentinvention comprise repeat units solely from polymerized allyl aminemonomers. More preferably, the polyallylamine polymers used in thepresent invention are homopolymers. Even more preferably, thepolyallylamine polymers used in the present invention are homopolymersof repeat units represented by Structural Formula (8). Polyallylaminepolymers used in the disclosed invention are preferably crosslinkedpolymers, more preferably crosslinked homopolymers.

In other embodiments, the aliphatic amine polymer can be a homopolymeror copolymer of polybutenylamine, polylysine, or polyarginine.

Preferably, the aliphatic amine polymer is rendered water-insoluble bycross-linking such as with a cross-linking agent. Suitable cross-linkingagents include those with functional groups which react with the aminogroup of the aliphatic amine monomer. Alternatively, the cross-linkingagent may contain two or more vinyl groups which undergo free radicalpolymerization with the amine monomer. In some cases the aliphatic aminepolymers are crosslinked after polymerization.

Aliphatic amine polymers are typically crosslinked with difunctionalcross-linking agents. Examples of suitable cross-linking agents includediacrylates and dimethylacrylates (e.g., ethylene glycol diacrylate,propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycoldimethacrylate, propylene glycol dimethacrylate, butylene glycoldimethacrylate, polyethyleneglycol dimethacrylate and polyethyleneglycoldiacrylate), methylene bisacrylamide, methylene bismethacrylamide,ethylene bisacrylamide, ethylene bismethacrylamide, ethylidenebisacrylamide, divinylbenzene, bisphenol A, the diglycidal ether ofbisphenol A, pyromellitic dianhydride, toluene diisocyanate, ethylenediamine and dimethyl succinate, dimethacrylate, and bisphenol Adiacrylate. Examples of preferred difunctional crosslinking agentsinclude epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane,1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride,dimethylsuccinate, toluene diisocyanate, acryloyl chloride, andpyromellitic dianhydride. Epichlorohydrin is a most preferredcrosslinking agent, because of its high availability and low cost.Epichlorohydrin is also advantageous because of its low molecular weightand hydrophilic nature, increasing the water-swellability and gelproperties of the polyamine. Epichlorohydrin forms 2-hydroxypropylcrosslinking groups.

Other methods of inducing crosslinking on already polymerized materialsinclude, but are not limited to, exposure to ionizing radiation,ultraviolet radiation, electron beams, radicals, and pyrolysis.

The level of cross-linking renders the aliphatic amine polymersinsoluble and substantially resistant to absorption and degradation,thereby limiting the activity of the aliphatic amine polymer to thegastrointestinal tract, and reducing potential side-effects in thepatient. Typically, the cross-linking agent is present in an amount fromabout 0.5-35% or about 0.5-25% (such as from about 2.5-20% or about1-10%) by weight, based upon total weight of aliphatic amine monomerplus cross-linking agent. Typically, the amount of cross-linking agentis measured as a percentage of the combined weight of aliphatic aminepolymer and crosslinking agent.

Typically, between about 9% and about 30% of the allylic nitrogen atomsare bonded to a crosslinking group, preferably between 15% and about21%.

The aliphatic amine polymers can also be further derivatized; examplesinclude alkylated amine polymers, as described, for example, in U.S.Pat. Nos. 5,679,717, 5,607,669 and 5,618,530, the teachings of which areincorporated herein by reference in their entireties. Preferredalkylating agents include hydrophobic groups (such as aliphatichydrophobic groups) and/or quaternary ammonium- or amine-substitutedalkyl groups.

Non-cross-linked and cross-linked polyallylamine and polyvinylamine aregenerally known in the art and are commercially available. Methods forthe manufacture of polyallylamine and polyvinylamine, and cross-linkedderivatives thereof, are described in the above U.S. Patents. Patents byHarada et al., (U.S. Pat. Nos. 4,605,701 and 4,528,347), which areincorporated herein by reference in their entireties, also describemethods of manufacturing polyallylamine and cross-linked polyallylamine.A patent by Stutts et al., (U.S. Pat. No. 6,180,754) describes anadditional method of manufacturing cross-linked polyallylamine.

The molecular weight of aliphatic amine polymers is not believed to becritical, provided that the molecular weight is large enough so that thealiphatic amine polymer is non-absorbable by the gastrointestinal tract.Typically, the molecular weight of aliphatic amine polymers is at least1090, For example the molecular weight can be from: about 1000 to about5 million, about 1000 to about 3 million, about 1000 to about 2 millionor about 1000 to about 1 million.

The aliphatic amine polymers used in the invention may be optionallyprotonated, and in one embodiment, include polymers in which less than40%, for example, less than 30%, such as less than 20% or less than 10%of the amine groups are protonated. In another embodiment 35% to 45% ofthe amines are protonated (e.g., approximately 40%). An example of asuitably protonated aliphatic amine polymer is sevelamer.

As described above, the aliphatic amine polymer can be administered inthe form of a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” refers to a salt of the aliphaticamine polymer to be administered prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids, organic acids,solvates, hydrates, or clathrates thereof. Thus, the nitrogen group inthe repeat unit of the aliphatic amine polymer is protonated to create apositively charged nitrogen atom associated with a negatively chargedcounterion.

Examples of suitable counterions include organic ions, inorganic ions,or a combination thereof. For instance, suitable counterions includehalides (e.g., F⁻, Cl⁻, Br⁻ and I⁻), CH₃OSO₃ ⁻, HSO₄ ⁻, SO₄ ²⁻, HCO₃ ⁻,CO₃ ²⁻, acetate, lactate, succinate, propionate, oxalate, butyrate,ascorbate, citrate, dihydrogen citrate, tartrate, taurocholate,glycocholate, cholate, hydrogen citrate, maleate, benzoate, folate, anamino acid derivative, a nucleotide, a lipid, or a phospholipid.Preferred anions are Cl⁻, HCO₃ ⁻, CO₃ ²⁻, and a combination thereof(e.g., a mixed carbonate and bicarbonate salt, a mixed carbonate andchloride salt, or a mixed bicarbonate and chloride salt). Thecounterions can be the same as, or different from, each other. Forexample, the polymer can contain two or more different types ofcounterions.

In a preferred embodiment, the aliphatic amine polymer used in thepresent invention is an epichlorohydrin cross-linked polyallylamine,such as sevelamer and colesevelam (see, for example, U.S. Pat. Nos.6,423,754; 5,607,669; and 5,679,717, the contents of which areincorporated herein by reference). In a preferred embodiment, thepolyallylamine polymer is crosslinked with epichlorohydrin and betweenabout 9% to about 30% (preferably about 15% to about 21%) of the allylicnitrogen atoms are bonded to a crosslinking group and the anion ischloride, carbonate or bicarbonate or a mixed salt thereof.

A particularly preferred aliphatic mine polymer is polyallylaminehydrochloride crosslinked with about 9.0-9.8% w/w epichlorohydrin,preferably 9.3-9.5%, and is the active chemical component of the drugknown as sevelamer HCl, sold under the tradename RENAGEL®. The structureis represented below:

where:

the sum of a and b (the number of primary amine groups) is 9;

c (the number of crosslinking groups) is 1;

n (the fraction of protonated amines) is 0.4; and

m is a large number (to indicate extended polymer network).

Another particularly preferred aliphatic amine polymer is polyallylaminehydrochloride crosslinked with epichlorohydrin and alkyated with1-bromodecane and (6-bromohexyl)-trimethylammonium bromide, referred toas colesevelam HCl, and marketed in the United States as WELCHOL®.

In yet another particularly preferred embodiment, the aliphatic aminepolymer is a carbonate salt of sevelamer; a bicarbonate salt ofsevelamer; a mixed carbonate and bicarbonate salt of sevelamer; or amixed carbonate and chloride salt of sevelamer.

In other embodiments, a monovalent anionic source is mixed with acarbonate salt of the aliphatic amine polymer. Various examples ofcarbonate salts of the aliphatic amine polymer and monovalent anionicsources are disclosed in U.S. Provisional Application No. 60/624,001“Aliphatic Amine Polymer Salts For Tableting” filed Nov. 1, 2004 andU.S. Provisional Application No. 60/628,752 “Aliphatic Amine PolymerSalts For Tableting” filed Nov. 17, 2004, the entire contents of whichare incorporated herein by reference.

The monovalent anion comprises at least 0.01%, preferably 0.05%, morepreferably a range of 0.01% to 2%, 0.05% to 1%, 0.08% to 0.5%, or 0.1%to 0.3% by weight of the combined weights of the carbonate salt ofaliphatic amine polymer and the monovalent anion source.

Examples of suitable monovalent anions include organic ions, inorganicions, or a combination thereof, such as halides (Cl⁻, I⁻, Fl⁻ and Br⁻),CH₃OSO₃ ⁻, HSO₄ ⁻, acetate, lactate, butyrate, propionate, sulphate,citrate, tartrate, nitrate, sulfonate, oxalate, succinate or palmoate.Preferred monovalent anions are halides, most preferably chloride.

Also, the monovalent anion source can be a pharmaceutically acceptableacid, ammonium or metal salt of a monovalent anion. Preferably themonovalent anion source is sodium chloride or hydrochloric acid. In onepreferred embodiment, the formulations of the invention comprise acarbonate salt of sevelamer and sodium chloride. In another preferredembodiment, the formulations of the invention comprise a carbonate saltof sevelamer and hydrochloric acid.

In yet another preferred embodiment, the monovalent anion source can bea monovalent anion salt of an aliphatic amine polymer comprising arepeat unit represented by Structural Formulas (1)-(8) above. Theformulations of the invention can comprise a “physically mixed polymer”or a “chemically mixed polymer”. The combination of a carbonate salt ofan aliphatic amine polymer and a monovalent anion salt of an aliphaticamine polymer is defined herein as a “physically mixed polymer”. Themonovalent anion salt of the aliphatic amine polymer can be the same ora different aliphatic amine polymer as the aliphatic amine polymercarbonate salt. Herein, a “chemically mixed polymer” means thecombination of a carbonate salt and a monovalent anion salt on a singlealiphatic amine polymer.

In some embodiments, the aliphatic amine polymer or pharmaceuticallyacceptable salt thereof is the only pharmaceutically active ingredientin the powder formulations.

The powder formulations of the invention for use in a subject comprisethe aliphatic amine polymer and the pharmaceutically acceptable anionicstabilizer(s), optionally together with one or more acceptableexcipients therefor. The excipients include carriers or diluents, suchas lactose, starch, cellulose and dextrose; flavoring agents;sweeteners; and preservatives, such as methyl, ethyl, propyl and butylparabens. Optionally, for a good appearance, excipients, such asmicrocrystalline cellulose, titanium dioxide, and/or coloring agents,such as FD&C Blue #1, FD&C Red #40, D&C Yellow #10, D&C Red #33, oryellow iron oxide, can also be included in the powder formulations ofthe invention. Examples of suitable sweeteners include sucrose; glucose(corn syrup); dextrose; invert sugar, fructose; saccharin and itsvarious salts, such as sodium saccharinate; sodium, aspartame, xylose;maltitol; maltol; potassium acesulfame; neohesperidin dihydrochalcone;monoammonium glycyrrhizinate; maltodextrin and polydextrose saccharinand its various salts such as the sodium and calcium salts; cyclamicacid and its various salts; dipeptide sweeteners; sucralose;dihydrochalcone; glycyrrhin; Stevia rebaudiana (Stevioside); sorbitol;mannitol; xylitol; hexa-resorcinol; hydrogenated starch hydrolysate(lycasin), and the potassium, calcium and sodium salts of3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-on3-2,2-dioxide, and a mixtureof thereof. Of the foregoing, sucralose, sucrose, xylose, mannitol,maltitol, maltol, sorbitol or xylitol is particularly preferred, eitheralone or more desirably in combination. Suitable flavorings includegrape, cherry, peppermint, menthol and vanilla flavors, such as orangevanilla flavor, lemon flavor, spearmint, wintergreen, cinnamon, menthoneflavors, or a mixture thereof. The excipients must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

Typically, the average particle size of the powder of the invention isless than 500 microns, preferably less than 200 microns. In someembodiments, the powder contains less than 5 wt %, preferably less than2 wt %, more preferably less than 1 wt %, of particles having a particlesize more than 300 microns and less than 5 wt %, preferably less than 2wt %, more preferably less than 1 wt %, of particles having a particlesize less than 10 microns.

The disclosed powder formulation is typically dissolved and/or suspendedin an ingestible liquid such as water. The resulting mixture has apleasant mouth-feel and therefore can be conveniently administered to apatient as a drink. The drink can be a suspension or solution. The drinkcan be even more palatable with one or more sweeteners and/orflavorants. Alternatively, the disclosed powder formulation can be mixedwith foods, such as mashed potatoes or oatmeal.

The powder formulations of the invention can be conveniently packaged ina container. Herein, a “container” is a non-ingestible containmentdevice which can hold and preserve the stability of the powderformulation of the invention for a sufficient period of time, i.e., fromthe time of manufacture to the time of consumption by patients. As notedabove, the powder formulation is uncapsulated and free-flowing.Containers suitable for the present invention include a sachet, such asa paper bag, powder bag of plastic films or metal foils; a bottle, suchas a glass, plastic or metal bottle; a tub; and an ampule. Preferably,the container of the invention is a sachet. The container material ispreferably impermeable to water and water vapor in order that thestability of the active agent contained in the container is ensured.Optionally, the container materials can contain substances which imparta particular type of protection, for example protection against light,to the contents. Examples of suitable container materials includeplastics, such as MATT LACQUER/PET 23μ/PX 12GR/AL 12μ/SURLYN 23GR (AMCORFlexibles in Victoria, Australia), coated papers, such as Coated Paper40GR/PX 12 GR/AL 12μ/SURLYN 23 GR (AMCOR Flexibles in Victoria,Australia), foil pouches, such as TPC-2475 (TOLAS Health Care Packagingin Feasterville, Pa.), and a combination of these materials (e.g.,laminates).

Preferably, the container is a multi-layer container having multiplelayers of different container materials discussed above.

The container containing the powder formulation of the invention can bea unit-dose or a multi-dose container. For example, the container of theinvention can contain a single dose of the aliphatic amine polymer mixedwith the pharmaceutically acceptable anionic stabilizer, such as asingle-dose sachet. Alternatively, the container of the invention cancontain at least two doses of the aliphatic amine polymer mixed with thepharmaceutically acceptable anionic stabilizer, such as a bottle or tubwith the powder formulation from which a unit dose is measured by, e.g.,a spoon or cup, or an instrument capable of dispensing a pre-defineddosage amount. Herein, a “tub” means a container containing a bulkquantity of the powder formulation. A “bulk quantity” means an amountout of which a plurality of unit doses can be divided, e.g., 2, 10, 50,100 or more unit doses.

The powder formulations of the invention can be prepared by any of themethods known in the art of pharmacy. For example, standardpharmaceutical formulation techniques such as those described inRemington's Pharmaceutical Sciences, 18th ed. (1990), Mack PublishingCompany, Easton, Pa., the disclosure of which is incorporated herein byreference, can be used. Typically, the methods include the steps ofmixing at least one aliphatic amine polymer with one or morepharmaceutically acceptable anionic stabilizers, and bringing intoassociation the resulting mixture with any additional excipients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing the aliphatic amine polymer into association with thepharmaceutically acceptable anionic stabilizers and then, if necessary,dividing the product into unit dosages thereof. The powder formulationis then packaged within a suitable container, such as a sachet.

Typically, the container holds a unit dose which is generally about 5 mgto about 15 g (e.g., 600 mg-7.5 g, 600 mg-5 g, 800 mg-3.5 g and 800mg-2.5 g) of the aliphatic amine polymer on an anhydrous basis ifadministered once a day. Typically, about 0.025 mg to about to about14.9 g (e.g., 3 mg-7.5 g; 3 mg-5 g; 8 mg-3.5 g; 8 mg-2.5 g; 6 mg-2.5 g,6 mg-1.5 g, 6 mg-0.75 g) of a pharmaceutically acceptable anionicstabilizer is included in the unit dose together with the aliphaticamine polymer. Alternatively, the container holds a unit dose which isgenerally the daily dosage divided by the number of administration perday if administered multiple times per day (e.g., 2, 3, 4, or 5times/day). In one example, a sachet contains either 800 mg, 1.6 g, 2.4g, 3.2 g, 4.0 g, 4.8 g, 5.6 g, 7.2 g or 9.6 g of sevelamer on ananhydrous basis, and further contains propylene glycol alginate andoptional excipients, such as sucrose, xylose, mannitol, maltitol,maltol, sodium chloride, yellow iron oxide, orange vanilla flavor andlemon flavor mixed with sevelamer.

The powder formulation may be introduced by a patient into a suitableamount of liquid, preferably water, to form a therapeutic formulation insitu, and the therapeutic formulation is then taken by the patient. Thetherapeutic formulation can be an aqueous-based therapeutic formulationor a non-aqueous formulation, preferably aqueous-based formulation, inwhich the aliphatic amine polymer and anionic stabilizer are eachindependently dissolved or suspended. Aqueous-based therapeuticformulations can be formed by adding the powder formulation within acontainer into a suitable aqueous vehicle, such as water, beforeadministration. Non-aqueous therapeutic formulations can be obtained bydispersing in a suitable non-aqueous based vehicle, such as almond oil,arachis oil, soybean oil, fractionated coconut oil, olive oil,poppy-seed oil or maize oil before administration. Alternatively, thepowder formulations of the invention may be administered by a patientvia direct ingestion. That is, a unit dose of the powder is administereddirectly into a mouth of the patient and then swallowed, preferably withthe aid of water or any other ingestible liquid. Optionally, the powderformulations of the invention may be administered by a patient as amixture with foods.

The powder formulations of the invention can be used for treatinghyperphospatemia in a subject. Hyperphosphatemia is typically definedfor humans as a serum phosphate level of greater than about 4.5 mg/dL.The condition, especially if present over extended periods of time,leads to severe abnormalities in calcium and phosphorus metabolism andcan be manifested by aberrant calcification in joints, lungs and eyes.Elevated serum phosphate is commonly present in patients with renalinsufficiency, hypoparathyroidism, pseudohypoparathyroidism, acuteuntreated acromegaly, overmedication with phosphate salts, and acutetissue destruction as occurs during rhabdomyolysis and treatment ofmalignancies.

As used herein a subject is a mammal, preferably a human, but can alsobe an animal in need of veterinary treatment, such as a companion animal(e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep,pigs, horses, and the like) or a laboratory animal (e.g., rats, mice,guinea pigs, and the like). A subject “in need of treatment” includes asubject with chronic renal failure. Other examples of subjects in needof treatment include patients with a disease associated with disordersof phosphate metabolism. Examples of diseases and/or disorders of thistype include hyperparathyroidism, inadequate renal function, andhyperphosphatemia.

An “effective amount” of an aliphatic amine polymer is a quantity thatresults in a beneficial clinical outcome of or exerts an influence on,the condition being treated with the aliphatic amine polymer comparedwith the absence of treatment. The amount of an aliphatic amine polymeradministered to the subject will depend on the degree, severity, andtype of the disease or condition, the amount of therapy desired, and therelease characteristics of the pharmaceutical formulation. It will alsodepend on the subject's health, size, weight, age, sex and tolerance todrugs. Typically, the composition of the invention is administered for asufficient period of time to achieve the desired therapeutic effect.Typically between about 5 mg per day and about 15 g per day of analiphatic amine polymer (alternatively between about 50 mg per day andabout 10 g per day, alternatively between about 1 g per day and about 10g per day, alternatively between about 1 g per day and about 8 g perday, alternatively between about 2 g per day and about 8 g per day,alternatively between about 4 g per day and about 8 g per day) isadministered to the subject in need of treatment. These dosages can beadministered several times/day (e.g., 2, 3, 4 or 5 times/day) oronce/day. The aliphatic amine polymer can be administered at least fourtimes per day with meals, at least three times per day with meals, atleast twice per day with meals, at least once per day with meals, (seeU.S. Provisional Application No. 60/623,985, “Once a day formulation forphosphate binders” filed Nov. 1, 2004, the entire contents of which areincorporated herein by reference). In one specific example, about0.8-7.2 g (e.g., 2.4 g or 3.2 g per dose for 2-3 times per day, or 4.0or 4.8 g per dose for 2-3 times per day, or 7.2 g per dose for once perday) of the aliphatic amine polymer is administered per day.

Typically, the formulations of the invention can be administered beforeor after a meal, or with a meal. As used herein, “before” or “after” ameal is typically within two hours, preferably within one hour, morepreferably within thirty minutes, most preferably within ten minutes ofcommencing or finishing a meal, respectively.

The method of the present invention includes a mono-therapy where thepowder formulations of the invention are used alone. The method of thepresent invention also includes a co-therapy with other therapeuticallyactive drugs. For example, the method of the present invention can beused with other phosphate binders including pharmaceutically acceptablelanthanum, calcium, aluminum and iron salts, such as acetates,carbonates, oxides, hydroxides, citrates, alginates, and ketoacids.Calcium salts, including calcium carbonate, acetate (such as PhosLo®calcium acetate tablets), citrate, alginate, and ketoacids, have beenutilized for phosphate binding. The ingested calcium combines withphosphate to form insoluble calcium phosphate salts such asCa₃(PO₄)_(z), CaHPO₄, or Ca(H₂PO₄)₂. Aluminium-based phosphate binders,such as Amphojel® aluminium hydroxide gel, have also been used fortreating hyperphosphatemia. These compounds complex with intestinalphosphate to form highly insoluble aluminium phosphate; the boundphosphate is unavailable for absorption by the patient. More recentlyiron and lanthanide salts have been used. The most commonly usedlanthanide salt, lanthanum carbonate (Fosrenol®) behaves similarly tocalcium carbonate.

Those skilled in the art will be aware that the amounts of the variouscomponents of the formulations of the invention to be administered inaccordance with the method of the invention to a subject will dependupon those factors noted above.

The invention is illustrated by the following examples which are notintended to be limiting in any way.

EXEMPLIFICATION Example 1. Compositions of Powder Formulations of theInvention

The powder formulations were prepared by standard pharmaceuticalformulation techniques such as those described in Remington'sPharmaceutical Sciences, 18th ed. (1990), Mack Publishing Company,Easton, Pa. Specific compositions of two exemplary powder formulations(Formulas A and B) of the invention are summarized in Table 1 below:

TABLE 1 Compositions of the powder formulations Formula FormulaIngredient A (wt %) B (wt %) Anhydrous Sevelemer HCl 92.90 AnhydrousSevelemer 94.97 carbonate PGA 1.00 3.00 Orange Vanilla PR90 2.00 2.00WG55 Vanilla 0.50 0.50 Lemon Lime 0.11 0.12 NaCl 1.00 1.00 Sucralose0.40 0.45 Yellow iron oxide 0.016 0.016

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-39. (canceled)
 40. A method of treating a patient suffering from anelevated serum phosphate level of 4.5 mg/dL or greater, comprising:administering to the patient a therapeutically effective amount ofpowder formulation comprising a mixture of: a) a pharmaceuticallyacceptable anionic stabilizer, wherein the pharmaceutically acceptableanionic stabilizer is an esterified alginate; b) carbonate salt ofsevelamer; and c) sodium chloride; wherein the only pharmaceuticallyactive ingredient in the powder is the sevelamer carbonate.
 41. Themethod of treating of claim 40, wherein the esterified alginate ispropylene glycol alginate.
 42. The method of treating of claim 40,wherein the amount of the sevelamer carbonate is 800 mg on an anhydrousbasis.
 43. The method of treating of claim 40, wherein the amount of thesevelamer carbonate is 2.4 g on an anhydrous basis.
 44. The method oftreating of claim 40, wherein the chloride of the sodium chloride ispresent in a range of between 0.01-2 wt. % relative to the combinedweights of the sevelamer carbonate and the sodium chloride.
 45. Themethod of treating of claim 40, wherein the chloride of the sodiumchloride is present in a range of between 0.05-1 wt. % relative to thecombined weights of the sevelamer carbonate and the sodium chloride. 46.The method of treating of claim 40, wherein the chloride of the sodiumchloride is present in a range of between 0.08-0.5 wt. % relative to thecombined weights of the sevelamer carbonate and the sodium chloride. 47.The method of treating of claim 40, wherein the powder is uncapsulatedand free-flowing, and wherein the powder contains less than 5 wt % ofparticles having a particle size more than 300 microns and less than 5wt % of particles having a particle size less than 10 microns.
 48. Themethod of treating of claim 40, wherein the powder formulation furthercomprises one or more of a pharmaceutically acceptable flavoring agent,sweetener, or coloring agent.
 49. The method of treating of claim 48,wherein the powder formulation further comprises a pharmaceuticallyacceptable flavoring agent.
 50. The method of treating of claim 49,wherein the pharmaceutically acceptable flavoring agent includes atleast one member selected from the group consisting of grape, cherry,peppermint, menthol, vanilla flavor, orange vanilla flavor, lemonflavor, spearmint, wintergreen, cinnamon, and menthone flavors.
 51. Themethod of treating of claim 50, wherein the at least onepharmaceutically acceptable flavoring agent is lemon flavor.
 52. Themethod of treating of claim 48, wherein the powder formulation furthercomprises a pharmaceutically acceptable sweetener.
 53. The method oftreating of claim 52, wherein the pharmaceutically acceptable sweetenerincludes at least one member selected from the group consisting ofsucralose, sucrose, xylose, mannitol, maltitol, maltol, sorbitol andxylitol.
 54. The method of treating of claim 53, wherein the at leastone pharmaceutically acceptable sweetener is sucralose.
 55. The methodof treating of claim 48, wherein the powder formulation furthercomprises a pharmaceutically acceptable coloring agent.
 56. The methodof treating of claim 55, wherein the pharmaceutically acceptablecoloring agent is yellow iron oxide.
 57. The method of treating of claim40, wherein the ratio of the anionic stabilizer to sevelamer carbonateis 0.005-1:1.
 58. The method of treating of claim 40, wherein thepatient suffers from hyperphosphatemia.
 59. The method of treating ofclaim 40, wherein the patient suffers from renal insufficiency,hypoparathyroidism, pseudohypoparathyroidism, acute untreatedacromegaly, overmedication with phosphate salts, or acute tissuedestruction from rhabdomyolysis.
 60. The method of treating of claim 59,wherein the patient suffers from renal insufficiency.
 61. The method oftreating of claim 40, wherein the therapeutically effective amount ofthe powder formulation is orally administered to the patient.
 62. Themethod of treating of claim 40, wherein the powder formulation ispackaged in a unit-dose container or a multi-dose container.
 63. Themethod of treating of claim 62, wherein the unit-dose container ormulti-dose container is a tub or sachet.